Method of preparing intermediates suitable for conversion into nuclear substituted heterocyclic compounds



Patented Apr. 18, 1950 I ED STATES PATENT [om-cs IVIIEITHOD OF PREPARING INTERMEDIATES SUITABLE FOR CONVERSION INTO NU- CLEAR SUBSTITUTED HETEROGYCLIG- COMPOUNDS Harold RL. Snyder and Robert E. Jones; Urbanalf ILL, assignors the Ullifi'd States (If Ameridt as representelil by the Secretary of'War No Drawin Application June 4, 1945'; v A Seria-l N0.597,587' "I B blaim's". (o1. 260=471) The" present invention relates generally to the synthesis of certain nuclear substituted quinoline N='oH-oH-oooR where X is anuclear substituent and Y is a carbalkoxy group, a cyano group or a substitutedcarbamyl group. Cyclization of "compounds of the foregoing type is accomplishedeither bylfusing the compound itself or by heating a dilute solution of the compound. in a high boiling' neutral or inert solvent such as diphenyl ether The process produces high yields of a substituted 4- hydroXy-guinoline: compound of the type II I y Y 7 a II- in carrying" out the foregoing synthesis; the starting materials I and IA of the type Where Sf is a substitutedcarbamyl group have heretofor'e been prepared bya two step process starting with a primary aromatic amine (III) and an orthoformic ester (IV). In the first step, 2 moles of the amine are c'ondens'edwith 1 mole or the orthoformic ester to form a formamidine type or compound (V) according to the scheme:

III 7 In the second step the formamidine compound is condensed with-malonic ester VI accordingto the scheme-: 7

X X 011, 0 0 on); -"-N=OHNH= p v i VI c.0011 Ne oe=e cows viI The foregoing method of preparing materials of" the type VII, although satisfactory from they wpoint of yield, is subject to the disa'dvantagefof group.

requiringtwo steps'for the synthesis of 'a com: pound which initself "is merely the startingm'a? terial in a mu1tip1e step synthesis of the desired compounds of the type II. v p 7 Broadly stated, the object of the prejs'ent in vention is to provide a new and improved methodof synthesizing compounds of the type Ar-nn -cnctcoon)-ooNHsr or their isomrian'ils ArN =CI-I-CH(COOR) -COI IHAr where Ar is anaryl radical and R is an alkyl A more particular object is the provision of an improved method of synthesizing intermediates of the type VIII'or their isomeric anils IX H coon Y ,N'H-oH=o'c o'NH' I viii V Y 0003 N=OH(EHCONH Iii Where Y is either hydrogen or one or more nuclear substituerits" including; inter aha};

halogen; alkyl, haloalkyl-and alkoxy radicals, and r R; isan alkyl group.

A still further object is" to synthesizecom pounds of the type VIII and IX in highyieldsgvm' a process involving essentially a single step, starting with readily available raw materials.

Other objects and advantages of thepresent invention vvill become apparent as the description progresses. I Y Y, p We'have fourid that 'the' foregoin'gfoh'j c't'siniay be" accomplished bythe process or the present invention which is based upon the discovery that the compounds of the type Ar--NHCH=C(COOR)-CONHAr or their isomeric anils if ArN=CH-CH(COOR-) CONHAr may be prepared essentially in one step by appropriate treatment of a reaction mixture containing about 2 moles of aprimary aromatic monoamine, about 1 mole of orthoformic ester and about 1 mole of malonic ester. At a temperature of the order of about 130 C. to about 170? C., this,

three-component reaction mixture reacts to form the desired type of compound, 4 moles of an al- I chloraniline and 16.0 g., (0.1 mole) of malonic ester were mixed in a small flask and heated at 150 C. on a hot plate. After forty-five minutes, 0.4 mole (23 cc.) of ethyl alcohol had distilled and heating was discontinued. After cooling,

. the oily liquid crystallized immediately upon addition of a traceiof the crystalline anilide. The solid was crushed into small pieces and washed three times with small portions of cold ethyl ether. The remaining solid (almost white) was sucked dry and was found to weight 24 g.; M. P. l05- ll0 0.. Mixed with an authentic sample, it

. melted at 109-114 C.

cohol being formed during the process. The reaction may be represented by the following overall'scheme:

2ArNH2+HC(OR) 3+CH2(COOR) 2- In carrying out the process of the present invention, the three-component reaction mixture is preferably heated under conditions permitting the distillation of the alcohol formed in the reaction, the temperature being maintained with-' in the range indicated until approximately the theoretical amount (4 moles) of alcohol have been collected. When the resulting reaction mixture is cooled, the desired compound usually separates as a solid and may be removed by filtration. V

The resulting solid product may be cyclized by heating a dilute solution thereof in a high boiling inert or neutral solvent, for example, mineral oil or diphenyl ether. This operation is preferably carried out under conditions permitting the distillation of a fifth mole of alcohol formed in the cyclization reaction, which may be represented by the following overall scheme:

.H' H Y 0002 Y -NHCH=COONH comr- The resulting anllide may be hydrolyzed to the corresponding free acid, for example, by treating the former with aqueous sulfuric acid of about 60 to 75% strength. The free "carboxylic' acid thus obtained may then be decarboxylated mere- -.The ether washings were evaporated and the oil dissolved in aqueous alcohol. Crystallization wasinduced by seeding and after cooling and filtration, an additional 5 g. of dry product was 7 obtained, M. P. 109-111 c. .The total yield was 29 g. (77 per cent).

2. Cyclization The productobtained in the preceding step was cyclized by refluxing for three hours a solution containing about 0.1 mole of acrylate in 1 liter of diphenyl ether. When the reaction mixture was cooled,light brown flakes crystallized. The m-chloranilide of 7-chloro-4-hydroxyquinoline-3-carboxylic acid thus obtained melted at 320-322". C., after recrystallization. The yield was 58% of the theoretical. When cycllzation was carried out at twice this dilution, a 75% yield was obtained.

3. Hydrolysis The anilide obtained in step 2 was hydrolyzed by refluxing for five minutes in 75% sulfuric acid -which converted the anilide to 7-chloro-4- hydroxyquinoline-3-carboxylic acid.

4. Decarboxylatz'on The acid obtained in step 3 was decarboxylated by fusion at 260-270 C. The fused mass, re-

crystallized from glacial acetic acid, gave 7- r chloro-4-hydroxyquinoline as large white prisms melting at 2825-2536" C. The mixed melting point with an authentic sample (M. P. 280.5-282 C.) was 282.5-286" C.

It will be apparent to those skilled in the art that many variations and modifications may be made in the detailed procedure described in the foregoing specific example. It will also be apparent that the basic principles of the present ly by fusing the free acid or by heating a solution of the free acid in a high boiling neutral solvent to a temperature of the order of the melting point of the acid.

In order more clearly to disclose the nature of the present invention a specific example will hereinafter be described in considerable detail. It should be clearly understood, however, that this is done solely by way of example and not for the purpose of delineating the scope of the invention or restricting the ambit of the appended claims.

EXAMPLE 1. Direct synthesis 0 Z-carbethoxy-S- (mchloram'lz'ne) -acryZo-m-chloranilide -F'ourteen and eight tenths grams (0.1 mole) of ethyl orthoformate, 25.6 g. (0.2 mole) of minvention may be applied to the preparation of compounds other than thoseherein specifically characterized. All such variations, modifications andextensions of the principles'of the present invention are to be understood as embraced with in the scope of the appended claims.

Having thus described our invention, what we claim as new and wish to secure by Letters Patent is:

1. In the preparation of compounds of the type where Y is at least one member of the group 7 consisting of hydrogen, alkylyhaloalkyl, halogen,

and 'alkoxy radicals, and R is a lower alkyl group, the improvement which comprises heating a reaction mixture containing about 2 molar equivalents of a primary aromatic monoamine of the typ about 1 molar equivalent of an orthoformic ester of the type HC(OR)a, and about 1 molar equivalent of a malonic ester of the type CH2(COOR) 2; said reaction mixture being heated to a temperature and for a time suflicient to cause the splitting out and distillation of about 4 molar equivalents of an alcohol therefrom.

2. In the preparation of compounds of the type about l molar equivalent of an orthoformic ester of the type HC(OR)a, about 1 molar equivalent or 6 a malonic ester of the type CHMCOORM; said mixture being maintained at a temperature of the order of about C. to about C. until about 4 molar equivalents of an alcohol ROH have distilled therefrom.

3. The method of claim 2 wherein said primary aromatic amine comprises m-chloraniline.

4. The method of claim 2 wherein said orthoformic ester comprises ethyl orthoformate and said malonic ester comprises ethyl malonate.

5. The method of claim 2 wherein said reaction mixture, after the distillation of said alcohol therefrom, is cooled and the solid reaction product is separated therefrom.

HAROLD R. SNYDER. ROBERT E. JONES.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,304,820 Hanford et a1 Dec. 15, 1942 2,351,391 Bergstrom et a1. June 18, 1944 FOREIGN PATENTS Number Country Date 42,276 Germany Jan. 19, 1888 7 OTHER REFERENCES Rubtsov: J. Gen. Chem. (U. S. S. R.), vol. '7, pp. 1885-1895 (1937). 

1. IN THE PREPARATION OF COMPOUNDS OF THE TYPE 